The implementation of combined antiretroviral therapy (cART) to treat HIV infection has been an incredible success and saved millions of lives. However, HIV remains a major public health issue and represents even today the leading cause of death globally in women with reproductive age (15-49 y) and the 2nd cause of death in adolescents in the world. The number of new infections is not sufficiently decreasing and a vaccine is urgently needed. Moreover, a cure for HIV is still lacking. In people living with HIV, cART treatment does not eliminate the virus from the body. Instead, the virus persists and hides in form of so-called “viral reservoirs”. As soon as cART is discontinued, the virus rebounds from the viral reservoirs and rapidly reaches viremia levels as high as before initiation of cART treatment. This persistence of HIV in cellular and anatomical reservoirs requires maintaining the treatment of HIV-infected individuals for their whole lives (Calin et al., 2016; Davey et al., 1999; Lorenzo-Redondo et al., 2016). Lifelong treatment represents a high economical cost. So far, only half of all patients worldwide have access to cART. Long-term efficacy of this treatment is also hampered by issues of drug resistance resulting from poor adherence. The operational and logistical challenges in delivering life-long treatment are indeed daunting. While second and third line drugs exist to combat resistant strains, they are often too expensive in the developing world. Viral load assays for clinical management of the patients and detection of viral resistance are most often not implemented (Chun et al., 2015; Trono et al., 2010). Last but not least, HIV infection is associated in many places with stigma and discrimination. If not diagnosed sufficiently early enough, cART is not capable to restore full immune function. Moreover, the persistent HIV-induced chronic inflammation in most cART-treated individuals induces a higher risk of non-AIDS mortality and co-morbidity.
This is why, HIV researchers have begun to explore a number of novel therapeutic strategiesin view of HIV cure. Many approaches (TLR-7, latency reversal agents, CMV vaccination, bNabs, anti-a4b7) are currently tested. The path toward a therapy for HIV cure is however very long. Multiple obstacles must be overcome to reach a persistent control or even elimination of HIV. In particular, HIV has a remarkable capacity to mutate and escape adaptive immune responses. Furthermore, HIV infection induces immunological dysfunction and consequently, the host fails to control viral replication. Moreover, the genetic material of the virus is integrated into the cellular genome, which allows the virus to become invisible and evade the host's immune responses. In this way, HIV can persist in the body for the whole life span of the host.
The case of Timothy Brown has raised hope that a HIV cure might nonetheless be feasible. Timothy Brown is an HIV-infected patient with cancer who received a double stem cell transplant from a donor whose CD4+ T cells were resistant to HIV infection thanks to a CCR5Δ32 mutation (Allers et al, 2011; Hutter et al, 2009). Since the transplantation 10 years ago, Timothy Brown is living without detectable virus and he represents the closest and only example to an HIV cure to date. However, achieving HIV eradication in a large population of patients with scalable and safe therapies seems farfetched at present.
More recently, cases of HIV remission have been described (Saez-Cirion et al., 2014). In analogy to cancer, HIV remission means that the while the virus is not eradicated, the patient is healthy, capable to control by its own the virus and does not need any drugs any more. HIV remission is also called functional cure. These few HIV-infected individuals in remission had started cART treatment early, already during the acute phase of infection, which is rather rare. Fourteen of these patients spontaneously controlled viral replication after cART interruption. Those patients had a small viral reservoir at the time of therapy interruption (Saez-Cirion et al., 2013). However, the patients did not show any particular strong classical B or T cell responses against HIV and thus the mechanisms of viral control leading to remission are unclear.
HIV originates from the Simian Immunodeficiency Virus (SIV) whose reservoir resides in African non human primates. Remarkably, the natural hosts of SIV, such as African green monkey (AGM), are resistant to AIDS (Chahroudi et al., 2012). This contrast with Asian monkeys (macaques) that are not infected in the wild and develop AIDS when infected with SIV (Garcia-Tellez et al., 2016; Ploquin et al., 2016). Similarly to HIV-infected individuals, SIVmac in macaques replicates to high levels in lymphoid tissues, in particular secondary lymphoid organs and intestinal mucosa. Important target cells for HIV and SIVmac viruses in these tissues are the central memory CD4 T cells (TCM) as well as transitional memory CD4 T cells (TTM) (Chomont et al., 2009; Descours et al., 2012). More recently though it has been shown that follicular helper CD4 T cells (TFH) that are localized in follicles of lymphoid tissues constitute the major reservoir of HIV and SIV (Banga, 2016; Buranapraditkun et al., 2017; Fukazawa et al., 2015; Miles and Connick, 2016a; Miles and Connick, 2016b; Moukambi et al., 2017).
SIV infection in AGM has been studied in order to identify factors responsible for protection against AIDS (Garcia-Tellez et al., 2016). Strikingly lymph nodes and spleen display extremely low levels of SIV in AGM (Brenchley et al., 2012; Gueye et al., 2004). SIVagm infection of TCM is rare and TFH are generally not infected at all in natural hosts (Brenchley et al., 2012; Cartwright et al., 2014; Paiardini et al., 2011; Ploquin et al 2016).
TFH cells are known to express high levels of HLA-E, the least polymorphic of all the MHC class Ib molecules. Under physiological conditions, HLA-E specifically binds the signal peptide derived from classical HLA class-Ia molecules, such as HLA-B. The expression of HLA-E at the cell surface is enhanced through the binding of such intracellular peptides. HLA-E interacts with CD94/NKG2A receptors expressed on the surface of natural killer (NK) cells and a small subset of CD8 T cells (Arlettaz et al., 2004). In addition, these CD8 T cells may specifically recognize foreign peptides presented by HLA-E and become activated through their T cell receptor (TCR), resulting in T cell activation, expansion, and memory formation in the adaptive immune system (Joosten et al., 2016). Presentation of the signal peptide by HLA-E protects the cell from being killed (Lee et al., 1998). In some situations, such as cellular stress and infections, HLA-E can bind other self-peptides such as the HSP60-derived peptides and also pathogen-derived sequences, rendering these cells more susceptible to attack by the innate and adaptive immune responses (Michaëlsson et al., 2002; Anraku et al., 2012).
HLA-E restricted CD8 T cells have been more studied in mice, where the molecule Qa-1 is the equivalent of HLA-E. The cells express effector cell markers, lymph node homing receptors and NK cell markers such as NKG2A, CD45RA, CCR7 and low levels of CXCR5 and ICOSL (He et al., 2016; Joosten et al., 2016; Kim et al., 2011; Lu and Cantor, 2008; Miles et al., 2016b). They also express CD122 and are IL-15-dependent. They play an important role in maintenance of self-tolerance and prevention of autoimmune disease (Kim et al., 2010; Long et al., 2017). In humans, a specific defect in the recognition of HLA-E/HSP60-peptides by HLA-E restricted CD8 T cells was associated with failure of self/non-self discrimination in type 1 diabetes, confirming that they play an important role in keeping self-reactive T cells in check (Jiang et al., 2010). In this regard, patients with type 1 diabetes harbor increased HSP60 levels (Devaraj et al., 2009; Shamaei-Tousi et al., 2006).
During lymphocytic choriomeningitis virus infection in mice, it has been shown that HLA-E restricted CD8 T cells can clear the persisting virus from TFH and B cells (He et al., 2016; Leong et al., 2016).
HIV-infection induces an enhanced expression of HLA-E resulting in reduced susceptibility to NK cell cytotoxicity (Nattermann et al., 2005). In some cases, the capacity to escape target cell lysis by NK cells, might outweight the potential risk of increased susceptibility to HLA-E-restricted CD8 T cells (Gong et al., 2012; Hansen et al., 2016; Joosten et al., 2016). HLA-E restricted CD8 T cells have been described in the tonsils of HIV-infected patients and in the lymph nodes and spleen of SIV-infected macaques and called “follicular regulatory CD8 T cells” (CD8 TFR) (Miles et al., 2016b). Their percentages increase with infection and lead to a potent impairment of TFH and germinal center B cell responses. HLA-E-restricted CD8 T cells are actually poorly primed during SIV/HIV infection. It is however not clear if these cells are the same than the HLA-E restricted CD8 T cells described in other studies or a new not yet described cell subset. We have (i) further characterized HLA-restricted T and NK cells (ii) studied if they can be experimentally induced by a drug in a non human primate model of HIV and (iii) analyzed the impact of this drug on viral load control during and after treatment cessation.